Modelling phagosomal lipid networks that regulate actin assembly

<p>Abstract</p> <p>Background</p> <p>When purified phagosomes are incubated in the presence of actin under appropriate conditions, microfilaments start growing from the membrane in a process that is affected by ATP and the lipid composition of the membrane. Isolated phagosomes are metabolically active organelles that contain enzymes and metabolites necessary for lipid interconversion. Hence, addition of ATP, lipids, and actin to the system alter the steady-state composition of the phagosomal membrane at the same time that the actin nucleation is initiated. Our aim was to model all these processes in parallel.</p> <p>Results</p> <p>We compiled detailed experimental data on the effects of different lipids and ATP on actin nucleation and we investigated experimentally lipid interconversion and ATP metabolism in phagosomes by using suitable radioactive compounds.</p> <p>In a first step, a complex lipid network interconnected by chemical reactions catalyzed by known enzymes was modelled in COPASI (Complex Pathway Simulator). However, several lines of experimental evidence indicated that only the phosphatidylinositol branch of the network was active, an observation that dramatically reduced the number of parameters in the model. The results also indicated that a lipid network-independent ATP-consuming activity should be included in the model. When this activity was introduced, the set of differential equations satisfactorily reproduced the experimental data. On the other hand, a molecular mechanism connecting membrane lipids, ATP, and the actin nucleation process is still missing. We therefore adopted a phenomenological (black-box) approach to represent the empirical observations. We proposed that lipids and ATP influence the dynamic interconversion between active and inactive actin nucleation sites. With this simple model, all the experimental data were satisfactorily fitted with a single positive parameter per lipid and ATP.</p> <p>Conclusion</p> <p>By establishing an active 'dialogue' between an initial complex model and experimental observations, we could narrow the set of differential equations and parameters required to characterize the time-dependent changes of metabolites influencing actin nucleation on phagosomes. For this, the global model was dissected into three sub-models: ATP consumption, lipid interconversion, and nucleation of actin on phagosomal membranes. This scheme allowed us to describe this complex system with a relatively small set of differential equations and kinetic parameters that satisfactorily reproduced the experimental data.</p

South American Expert Roundtable : increasing adaptive governance capacity for coping with unintended side effects of digital transformation

This paper presents the main messages of a South American expert roundtable (ERT) on the unintended side effects (unseens) of digital transformation. The input of the ERT comprised 39 propositions from 20 experts representing 11 different perspectives. The two-day ERT discussed the main drivers and challenges as well as vulnerabilities or unseens and provided suggestions for: (i) the mechanisms underlying major unseens; (ii) understanding possible ways in which rebound effects of digital transformation may become the subject of overarching research in three main categories of impact: development factors, society, and individuals; and (iii) a set of potential action domains for transdisciplinary follow-up processes, including a case study in Brazil. A content analysis of the propositions and related mechanisms provided insights in the genesis of unseens by identifying 15 interrelated causal mechanisms related to critical issues/concerns. Additionally, a cluster analysis (CLA) was applied to structure the challenges and critical developments in South America. The discussion elaborated the genesis, dynamics, and impacts of (groups of) unseens such as the digital divide (that affects most countries that are not included in the development of digital business, management, production, etc. tools) or the challenge of restructuring small- and medium-sized enterprises (whose service is digitally substituted by digital devices). We identify specific issues and effects (for most South American countries) such as lack of governmental structure, challenging geographical structures (e.g., inclusion in high-performance transmission power), or the digital readiness of (wide parts) of society. One scientific contribution of the paper is related to the presented methodology that provides insights into the phenomena, the causal chains underlying “wanted/positive” and “unwanted/negative” effects, and the processes and mechanisms of societal changes caused by digitalization

Effects of a co-designed exercise and sport intervention on cardiorespiratory fitness and metabolic syndrome components among individuals living in a refugee camp in Greece: A randomized controlled trial.

BACKGROUND The metabolic syndrome epidemic, including in forcibly displaced individuals, requires cost-effective prevention and treatment strategies. Yet, the health needs of forcibly displaced individuals often remain underserved. Our study evaluated the effect of a co-designed exercise and sport intervention on cardiorespiratory fitness and metabolic syndrome components among individuals in a refugee camp in Greece and examined the indirect effect through cardiorespiratory fitness on metabolic syndrome components. METHODS We conducted a randomized controlled trial involving an intervention and a wait-list control group with n = 142 (52.8 % women) forcibly displaced Southwest Asians and Sub-Saharan Africans. The intervention group participated for 10 weeks in exercise and sport activities. Outcomes were cardiorespiratory fitness and single metabolic syndrome components. Effects were analyzed with structural equation modeling. RESULTS In total, 62.7 % of participants presented with low cardiorespiratory fitness levels (<40th percentile), and 24.6 % met the criteria for metabolic syndrome. In the intervention group, 73.5 % attended the exercise and sport sessions at least once a week. There was evidence for a direct intervention effect on cardiorespiratory fitness, ßdirect = 0.12, p = 0.022, but not for any of the metabolic syndrome components (p ≥ 0.192). Cardiorespiratory fitness significantly facilitated the intervention's indirect effect on abdominal obesity, ßindirect = -0.03, p = 0.012, high diastolic blood pressure, ßindirect = -0.04, p = 0.011, and elevated triglycerides, ßindirect = -0.03, p = 0.025. CONCLUSION Implementing exercise and sport activities in a refugee camp in Greece effectively reaches a wider target population and improves cardiorespiratory fitness among forcibly displaced individuals. The intervention contributes to a decrease in abdominal obesity, high diastolic blood pressure and elevated triglycerides indirectly via improved cardiorespiratory fitness

Associations between grip strength, cardiorespiratory fitness, cardiovascular risk and mental health in forcibly displaced people from a Greek refugee camp.

Muscular strength represents a specific component of health-related fitness. Hand grip strength is used as a simple and dynamic marker of maximum voluntary force of the hand and to estimate overall strength. Today, little is known about the relationship between grip strength and health in forcibly displaced populations. In the present study, we examined whether grip strength is associated with various health outcomes in a sample of forcibly displaced people living in a Greek refugee camp. The present analyses are part of a larger pragmatic randomized controlled trial. In this paper, cross-sectional baseline data of 143 participants (71 men, 72 women) will be presented. In addition to grip strength, the following physical and mental health outcomes were assessed: body weight and body composition, blood pressure, total cholesterol, low- and high-density lipoprotein cholesterol, triglycerides, blood glucose levels (HbA1c), post-traumatic stress disorder (PTSD) symptoms, depressive and anxiety symptoms, pain, and quality of life. Linear regression analyses were carried out to examine how grip strength is associated with the health outcomes, separately for absolute and normalized grip strength scores. Grip strength was positively and strongly associated with percentage muscle mass (normalized grip strength: Stand. B = 0.58, p < .001), whereas a negative association existed for percentage body fat (normalized grip strength: Stand. B = - 0.58, p < .001). No statistically significant associations occurred between grip strength and the other cardiovascular risk markers. In contrast, we found that participants with higher normalized grip strength reported higher levels of PTSD (normalized grip strength: Stand. B = 0.36, p < .05) and depressive symptoms (normalized grip strength: Stand. B = 0.29, p < .05). No significant association occurred between grip strength, anxiety, pain and quality of life. Measuring grip strength in forcibly displaced people can be a useful way to assess their overall muscle strength. Grip strength tests are easy to implement, and results can be used to assess the effects of specific intervention measures. Nevertheless, our results question the usefulness of grip strength as a marker of cardiovascular health and mental wellbeing in a refugee camp setting

Effects of an exercise and sport intervention among refugees living in a Greek refugee camp on mental health, physical fitness and cardiovascular risk markers: study protocol for the SALEEM pragmatic randomized controlled trial

Background Due to ongoing political and social conflicts, the number of international refugees has been increasing. Refugees are exposed to severe mental and physical strain, as well as traumatic experiences during their flight. Therefore, the risk of psychiatric disorders is markedly increased among international refugees. International organizations have criticized the lack of early interventions as a key problem, because untreated mental disorders are often difficult to cure at a later stage. Today, exercise and sport have been successfully employed to treat a wide range of psychiatric disorders. With patients with post-traumatic stress disorders (PTSD), very limited empirical evidence exists, and studies carried out with international refugees are nearly non-existent. Methods We intend to implement a pragmatic randomized controlled trial (RCT) with an exercise and sport intervention group (n = 68, 50% women) and a wait-list control group (n = 68, 50% women) in the Koutsochero refugee camp, located close to the city of Larissa (Greece). During the RCT, exercise and sport will be offered five times per week (60 min/session) for 10 weeks. Participants will be asked to participate in at least two sessions per week. The programme is developed according to the participants’ needs and preferences and they will be able to choose between a range of activities. PTSD symptoms will serve as primary outcome, and several secondary outcomes will be assessed. Qualitative data collection methods will be used to gain a more in-depth appraisal of the participants’ perception of the intervention programme. In the second year of study, the programme will be opened to all camp residents. A strategy will be developed how the programme can be continued after the end of the funding period, and how the programme can be scaled up beyond the borders of the Koutsochero camp. Discussion By moving towards the primary prevention of chronic physical conditions and psychiatric disorders, a relevant contribution can be done to enhance the quality and quantity of life of refugee camp residents in Greece. Our findings may also strengthen the evidence for exercise as medicine as a holistic care option in refugee camps, by helping camp residents to adopt and maintain a physically active lifestyle. Trial registration The study was registered prospectively on the 8 February 2021 with ISRCTN https://www.isrctn.com/ISRCTN1629198

Psychological well-being, mental distress, metabolic syndrome, and associated factors among people living in a refugee camp in Greece: a cross-sectional study

BackgroundForcibly displaced people face various challenges and are therefore at higher risk of being affected by mental and physiological distress. The present study aimed to determine levels of psychological well-being, PTSD symptom severity, metabolic syndrome, and associated factors among forcibly displaced people in Greece in response to WHO’s call for evidence-based public health policies and programs for forcibly displaced people.MethodsWe conducted a cross-sectional study among n = 150 (50% women) forcibly displaced people originating from Sub-Sahara Africa and Southwest Asia living in a Greek refugee camp. Self-report questionnaires were used to assess psychological well-being, symptoms of PTSD, depression, generalized anxiety disorder and insomnia, perceived stress, headache, and perceived fitness. Cardiovascular risk markers were assessed to determine metabolic syndrome, and cardiorespiratory fitness was measured with the Åstrand-Rhyming Test of Maximal Oxygen Uptake.ResultsThe prevalence of mental distress and physiological disorders was overall elevated. Only 53.0% of participants rated their psychological well-being as high. Altogether, 35.3% scored above the clinical cut-off for PTSD, 33.3% for depression, 27.9% for generalized anxiety disorder, and 33.8% for insomnia. One in four (28.8%) participants met criteria for metabolic syndrome. While the prevalence of moderate or severe insomnia symptoms and metabolic syndrome differed little from the global population, the risk of being affected by mental distress was markedly increased. In multivariable analysis, higher perceived fitness was associated with higher psychological well-being (OR = 1.35, p = 0.003) and a decreased likelihood for metabolic syndrome (OR = 0.80, p = 0.031). Participants with elevated psychiatric symptoms were less likely to report high psychological well-being (OR = 0.22, p = 0.003) and had increased odds for higher PTSD severity (OR = 3.27, p = 0.034). Increased stress perception was associated with higher PTSD symptoms (OR = 1.13, p = 0.002).ConclusionThere is an elevated risk for mental distress compared to the global population and an overall high mental and physiological burden among people living in a Greek refugee camp. The findings underpin the call for urgent action. Policies should aim to reduce post-migration stressors and address mental health and non-communicable diseases by various programs. Sport and exercise interventions may be a favorable add-on, given that perceived fitness is associated with both mental and physiological health benefits

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Neurons are MHC Class I-Dependent Targets for CD8 T Cells upon Neurotropic Viral Infection

Following infection of the central nervous system (CNS), the immune system is faced with the challenge of eliminating the pathogen without causing significant damage to neurons, which have limited capacities of renewal. In particular, it was thought that neurons were protected from direct attack by cytotoxic T lymphocytes (CTL) because they do not express major histocompatibility class I (MHC I) molecules, at least at steady state. To date, most of our current knowledge on the specifics of neuron-CTL interaction is based on studies artificially inducing MHC I expression on neurons, loading them with exogenous peptide and applying CTL clones or lines often differentiated in culture. Thus, much remains to be uncovered regarding the modalities of the interaction between infected neurons and antiviral CD8 T cells in the course of a natural disease. Here, we used the model of neuroinflammation caused by neurotropic Borna disease virus (BDV), in which virus-specific CTL have been demonstrated as the main immune effectors triggering disease. We tested the pathogenic properties of brain-isolated CD8 T cells against pure neuronal cultures infected with BDV. We observed that BDV infection of cortical neurons triggered a significant up regulation of MHC I molecules, rendering them susceptible to recognition by antiviral CTL, freshly isolated from the brains of acutely infected rats. Using real-time imaging, we analyzed the spatio-temporal relationships between neurons and CTL. Brain-isolated CTL exhibited a reduced mobility and established stable contacts with BDV-infected neurons, in an antigen- and MHC-dependent manner. This interaction induced rapid morphological changes of the neurons, without immediate killing or impairment of electrical activity. Early signs of neuronal apoptosis were detected only hours after this initial contact. Thus, our results show that infected neurons can be recognized efficiently by brain-isolated antiviral CD8 T cells and uncover the unusual modalities of CTL-induced neuronal damage

PREDICT identifies precipitating events associated with the clinical course of acutely decompensated cirrhosis

Background & Aims: Acute decompensation (AD) of cirrhosis may present without acute-on-chronic liver failure (ACLF) (ADNo ACLF), or with ACLF (AD-ACLF), defined by organ failure(s). Herein, we aimed to analyze and characterize the precipitants leading to both of these AD phenotypes. Methods: The multicenter, prospective, observational PREDICT study (NCT03056612) included 1,273 non-electively hospitalized patients with AD (No ACLF = 1,071; ACLF = 202). Medical history, clinical data and laboratory data were collected at enrolment and during 90-day follow-up, with particular attention given to the following characteristics of precipitants: induction of organ dysfunction or failure, systemic inflammation, chronology, intensity, and relationship to outcome. Results: Among various clinical events, 4 distinct events were precipitants consistently related to AD: proven bacterial infections, severe alcoholic hepatitis, gastrointestinal bleeding with shock and toxic encephalopathy. Among patients with precipitants in the AD-No ACLF cohort and the AD-ACLF cohort (38% and 71%, respectively), almost all (96% and 97%, respectively) showed proven bacterial infection and severe alcoholic hepatitis, either alone or in combination with other events. Survival was similar in patients with proven bacterial infections or severe alcoholic hepatitis in both AD phenotypes. The number of precipitants was associated with significantly increased 90day mortality and was paralleled by increasing levels of surrogates for systemic inflammation. Importantly, adequate first-line antibiotic treatment of proven bacterial infections was associated with a lower ACLF development rate and lower 90-day mortality. Conclusions: This study identified precipitants that are significantly associated with a distinct clinical course and prognosis in patients with AD. Specific preventive and therapeutic strategies targeting these events may improve outcomes in patients with decompensated cirrhosis. Lay summary: Acute decompensation (AD) of cirrhosis is characterized by a rapid deterioration in patient health. Herein, we aimed to analyze the precipitating events that cause AD in patients with cirrhosis. Proven bacterial infections and severe alcoholic hepatitis, either alone or in combination, accounted for almost all (96-97%) cases of AD and acute-on-chronic liver failure. Whilst the type of precipitant was not associated with mortality, the number of precipitant(s) was. This study identified precipitants that are significantly associated with a distinct clinical course and prognosis of patients with AD. Specific preventive and therapeutic strategies targeting these events may improve patient outcomes. (c) 2020 European Association for the Study of the Liver. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)